Biology subjects

Artichoker, J.

Publications and source records attributed to Artichoker, J..

2 recordsLinked to original sources

bioRxiv2021

Spatiotemporal co-dependency between macrophages and exhausted CD8+ T cells in cancer

T cell exhaustion is a major impediment to anti-tumor immunity. However, it remains elusive how other immune cells in the tumor microenvironment (TME) contribute to this dysfunctional state. Here we show that the biology of tumor-associated macrophages (TAM) and exhausted T cells (Tex) in the TME is extensively linked. We demonstrate that in vivo depletion of TAM reduces exhaustion programs in tumor-infiltrating CD8+ T cells and reinvigorates their effector potential. Reciprocally, transcriptional and epigenetic profiling reveals that Tex express factors that actively recruit monocytes to the TME and shape their differentiation. Using lattice light sheet microscopy, we show that TAM and CD8+ T cells engage in unique long-lasting antigen-specific synaptic interactions that fail to activate T cells, but prime them for exhaustion, which is then accelerated in hypoxic conditions. Spatially resolved sequencing supports a spatiotemporal self-enforcing positive feedback circuit that is aligned to protect rather than destroy a tumor. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/461866v1_ufig1.gif" ALT="Figure 1"> View larger version (65K): org.highwire.dtl.DTLVardef@1fb1c4aorg.highwire.dtl.DTLVardef@fe4571org.highwire.dtl.DTLVardef@1812f76org.highwire.dtl.DTLVardef@5317d5_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2021

Active Surveillance Characterizes Human Intratumoral T Cell Exhaustion

Intratumoral T cells that might otherwise control tumors are often identified in an exhausted state, defined by specific epigenetic modifications as well as upregulation of genes such as CD38, CTLA-4 and PD-1. While the term might imply inactivity, there has been little study of this state at the phenotypic level in tumors to understand the extent of their incapacitation. Starting with the observation that T cells move more quickly through mouse tumors as residence time increases and they progress towards exhaustion, we elaborated a non-stimulatory live-biopsy method for real-time study of T cell behaviors within individual patient tumors. Using two-photon microscopy, we studied native CD8 T cells interacting with APCs and with cancer cells in different micro-niches of human tumors, finding that T cell speed was variable by region and by patient, was independent of T cell density and was inversely correlated with local tumor density. Across a range of tumor types, we found a strong relationship between CD8 T cell motility and exhausted T cell state that corresponds to observations made in mouse models where exhausted T cells move faster. While this is a small study, it demonstrates at least two types of T cell dynamic states in individual human tumors and supports the existence of an active program in exhausted T cells that extends beyond incapacitating them.

immunology↗